The overall objective of this project is to understand the physical factors determining resistance to blood flow in networks of microvessels. Previous studies have shown that flow resistance in living microvessels is substantially higher than in uniform glass tubes with corresponding diameters. The main reasons for this difference are believed to be the irregularity of the pathways traversed by red blood cells, and the presence of an endothelial surface layer (glycocalyx) lining microvessel walls, which restricts the flow. It is proposed to develop and test quantitative theoretical models relating flow resistance in microvessels to the mechanics of red blood cells and the glycocalyx. Flow resistance also depends on the architecture of microvascular networks. Microvascular networks show adaptive responses to mechanical forces, including transmural pressure and wall shear stress, and to metabolic stimuli. It is proposed to develop theoretical modelsor vascular network adaptation in response to these stimuli. The specific aims are: l.To develop models for the motion of red blood cells along uniform capillaries lined with a glycocalyx, which will be represented as a deformable, porous medium. Single-file motion of red blood cells through the capillary will be modeled, taking into account cell deformation. The contribution of the glycocalyx to the resistance to blood flow in capillaries will be estimated.2. To develop models for the transient motion and deformation of red cells traversing non-uniform microvessels, including the effects of the glycocalyx. The energy required to drive a red blood cell through capillaries with non-uniform cross-sections will be computed. Effects of the glycocalyx and of transient deformation of red cells will be considered. 3.To develop models for microvascular network adaptation in response to hemodynamic and metabolic stimuli. These models will used to predict the effects of vascular adaptive responses on the distribution of vessel diameters and on the stability of observed network structures. The predictions will compared with detailed observations of network architecture. Emphasis will be placed on comparing the results with experimental findings, and on examining their physiological implications in normal states and in conditions involving impaired microvascular flow and/or changes in red blood cell or plasma properties. This will be facilitated by well-established and active collaborations with experimental hemorheologists and physiologists.